Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic ...tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity.
Display omitted
•Abemaciclib monotherapy induces intra-tumor T cell inflammatory signature•Treatment causes MHC class I and II upregulation in tumor cells and increased NFAT signaling in T cells•Synergy with PD-L1 checkpoint blockade enhances adaptive and innate immune activation•Combination therapy leads to complete tumor rejection and immunological memory
Schaer, Beckmann et al. describe unique immune-modulating properties of abemaciclib that include upregulation of antigen presentation on tumor cells and increased T cell activation. These activities synergize with anti-PD-L1 therapy to further enhance immune activation, including macrophage and DC antigen presentation, and also lead to a reciprocal increase in abemaciclib-dependent cell cycle gene regulation.
CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation ...as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.
Ongoing research is necessary to better understand the causes of autism spectrum disorder (ASD), the developmental outcomes for individuals diagnosed with ASD, and the efficacy of the interventions. ...However, it is often difficult to recruit sufficient numbers of participants for studies, and despite the prevalence of ASD (currently estimated to affect 1 in 54 children), little research has focused on how to efficiently recruit participants with ASD.
The aim of this study was to determine the efficacy of two different paid advertisements-social media and radio advertising-in recruiting participants for a study enrolling people with ASD and their family members by examining the number of participants enrolled, the cost per participant, and the geographic reach of each type of advertising.
We examined participant enrollment in a study following nonoverlapping paid advertisements on a popular FM radio station (aired in three cities across two states) and Facebook (six advertisements that ran in five cities across two states). The total paid investment in the radio campaign was $12,030 and that in the Facebook campaign was $2950. Following the advertising campaigns, 1391 participants in the study who were affiliated with the Houston, Texas, site received email invitations to participate in a brief survey about the ways in which they learned about the study (eg, social media, medical provider, website) and which of these were most influential in their decisions to participate; 374 (26.8%) of the participants completed this survey.
Social media advertising outperformed radio in all three parameters examined by enrolling more participants (338 vs 149), with a lower average cost per participant ($8.73 vs $80.74) and a wider geographic reach, based on a comparison of the number of zip codes within and outside of Texas for questionnaire respondents who rated social media as the most influential method of contact (n=367, χ
=5.85, P=.02). Of the 374 survey participants, 139 (37.2%) reported that they had seen the study on social media prior to enrollment, while only 9 (2.4%) said they heard about it via radio.
Our findings suggest that advertising on social media can efficiently reach a large pool of potential participants with ASD, increasing the likelihood of meeting study enrollment goals. Researchers should consider allocating at least some portion of recruitment dollars to social media platforms as a means of quickly and inexpensively reaching out to their target populations, including for studies with in-person procedures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The
fusion transcription factor that drives ES pathobiology was ...previously demonstrated to modulate cyclin D1 expression. In this study, we evaluated abemaciclib, a small-molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES.
Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the
response of ES cell lines to abemaciclib. We then evaluated abemaciclib
in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of ES as either a monotherapy or in combination with chemotherapy.
Abemaciclib induced quiescence in ES cell lines via a G
cell-cycle block, characterized by decreased proliferation and reduction of Ki-67 and FOXM1 expression and retinoblastoma protein (RB) phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single-agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed.
Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.
The own-gender bias in face recognition has been hypothesized to be the result of extensive experience with own-gender faces, coupled with a motivation to process own-group faces more deeply than ...other-group faces. We test the effect of experience and motivation in four experiments employing standard old/new recognition paradigms. In Experiment 1, no own-gender recognition bias was observed following an attractiveness-rating encoding task regardless of school type (single- or mixed-sex). Experiment 2, which used a distinctiveness-rating encoding task, did find a significant own-gender bias for all groups of participants. Experiment 3 on adults found that the own-gender bias was not affected by self-reported contact with the other-gender, but the encoding task did moderate the size of the bias. Experiment 4 revealed that participants with an own-gender sexual orientation showed a stronger own-gender bias. These results indicate that motivational factors influence the own-gender bias whereas no evidence was found for perceptual experience.
Public Significance Statement
This study suggests that the biases that exist in face perception (the bias toward recognizing faces of one's own gender) may be due to how interested we are in processing those types of faces. To reduce biases toward recognizing faces of one's own group, we must have sufficient motivation to process other-group faces deeply.
School-based agricultural education (SBAE) teachers have been encouraged to use a variety of instructional methods. Despite teacher education programs covering numerous instructional methods and ...promoting active teaching strategies, prior research has indicated teachers’ predominant use of teacher-centered methods. Guided by social cognitive theory, we sought to determine relationships between teachers’ use of instructional methods, belief of method effectiveness, and teacher characteristics. We developed a web survey and administered it to all Florida SBAE teachers. We analyzed 146 usable responses using means, standard deviations, frequencies, zero order correlations, and mixed selection step-wise linear regressions. Findings indicated the most commonly used teaching methods were lecture-discussion, cooperative learning, demonstration, and paired/small group discussion. Teachers believed demonstration and cooperative learning to be most effective and debate and role-play least effective. Significant and positive correlations were found between belief of method effectiveness and method use for lecture-discussion, cooperative learning, demonstration, and paired/small group discussion. Regression models revealed similar trends, with the exception of lecture-discussion. We recommend pre-service and in-service teacher education programs emphasize the importance of student-centered instruction. In this effort, facilitators of teacher education programs should recognize the positive relationships between teachers’ beliefs of a method’s effectiveness and use of that method.
Limited research exists on the association between stress, coping, and binge eating. To address this paucity, this study explores these associations in a sample of 147 female college students, an ...at-risk population for binge eating. We hypothesized that emotional and avoidant coping would be positively associated with stress and binge eating. Conversely, we expected that rational and detached coping would be negatively related to stress and binge eating. Furthermore, we expected these coping styles to mediate the relationship between stress and binge eating. As predicted, emotion-focused and avoidant coping were positively associated with stress and binge eating. Additionally, emotion-focused coping partially mediated the relationship between stress and binge eating. However, no association was found between stress, rational or detached coping, and binge eating. These results are discussed within the context of a negative reinforcement model of binge eating. Lastly, the importance of providing evidence-based treatment for individuals with binge eating symptomology is discussed in light of our findings.
► Emotion-focused and avoidant coping were positively associated with stress and binge eating. ► Emotion-focused coping partially mediated the relationship between stress and binge eating. ► No association was found between stress, rational or detached coping, and binge eating.
Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to ...mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity
and
, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.
Ink Trails II Dempsey, Dave; Dempsey, Jack
03/2016
eBook
From authors of bodice rippers and gallant figures to hometown poetry, hearty men, and tales of American originals, the history of literature in Michigan is deep and rich. The Wolverine State has ...been the birthplace, home, and inspiration to a tremendous number of men and women of letters, both the well-known and the obscure.Ink Trails IItells the stories of these fascinating and diverse writers whose talent is inextricably linked to Michigan.Exploring the hidden treasures of otherwise forgotten authors while also acknowledging the Michigan-set stories of giants like Hemingway, Dave and Jack Dempsey delve into the state's literary heritage, as robust, diverse, and inexhaustible as the natural beauty of the place that nurtured it. This second volume of "ink trails" continues to tell the story of the remarkable writers, powerful words, and sublime nature of Michigan in the same well-researched and entertaining prose as the first.
PDF
